4R00MH109627; PI: Lemos, Julia Modified Project Summary/Abstract Section The objective of this ?Pathway to Independence? award is to determine the cellular, circuit and behavioral actions of the neuropeptide corticotropin releasing factor (CRF) in the nucleus accumbens (NAc) in stress-nave and stress-exposed mice. CRF modulates neuronal activity within limbic nuclei independently of its canonical actions as the initiation factor for the hypothalamic-pituitary-adrenal (HPA) axis. The NAc integrates cognitive, limbic and motor inputs to motivate behavior. Despite indications that CRF system and the NAc are important in the etiology of depression-related behaviors, they have been mostly studied independently. However, it was recently demonstrated that CRF increases dopamine in the NAc to produce appetitive behaviors. Moreover, in stress-exposed animals CRF?s capacity to enhance dopamine is ablated and intra-accumbal CRF is now perceived as aversive. It is thought that dopamine can influence the net output of the NAc by modulating the excitability of principal projection neurons, medium spiny neurons (MSNs) by modifying glutamatergic synaptic strength and plasticity at corticolimbic synapses as well as intrinsic properties and calcium dynamics of MSNs. Based on the observation that CRF normally enhances dopamine, I hypothesize that CRF modulates the excitability of MSNs via a dopamine-dependent mechanism to promote appetitive actions. Furthermore, in stress-exposed animals, in which CRF no longer increases dopamine release, I hypothesize CRF regulation of MSNs is altered such that CRF now promotes avoidant behaviors. To test these hypotheses, I propose two specific aims. Specific Aim 1: Determine the effects of CRF on the excitability of MSNs in the NAc of stress-nave and stress-exposed mice. Aim 1 seeks investigate the acute modulatory effects of CRF on NAc MSN excitability and ensemble activity using a combination of calcium imaging and electrophysiology. These experiments will be conducted in mice with different stressor exposure (nave, subchronic stress, chronic stress) or with chronic exposure to intra-NAc infusions of CRF. The primary goal of Aim 1 is to identify CRF mediated changes in MSN function that are unique to animals that have be previously exposed to stress in order to understand the cellular mechanism underlying the switch in motivational valence of NAc CRF. Specific Aim 2: Determine the effect of endogenously release CRF in the NAc on motivated behavior in stress-nave and stress exposed mice. In the second aim, I will use a novel conditional CRF{loxP/loxP} mouse to delete CRF peptide selectively in the NAc of adult mice. I will assess the effects of this NAc CRF deletion on dopamine-dependent exploratory and reward-seeking behaviors. I will build on this foundation and assess the effects of NAc CRF deletion on more complex dopamine-dependent decision-making behaviors using assays that examine risk-attitude and reward learning under changing contingencies. The primary goal of Aim 2 is to determine the role of endogenous, locally released NAc CRF in motivating specific actions under changing conditions and to assess impaired decision-making, a behavioral corollary of depression.